Hoffmann G F, Zschocke J
Department of Neuropaediatrics and Metabolic Diseases, Philipps University, Marburg, Germany.
J Inherit Metab Dis. 1999 Jun;22(4):381-91. doi: 10.1023/a:1005543904484.
The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.
由于戊二酰辅酶A脱氢酶缺乏导致的I型戊二酸尿症（GA I）的生化特征是戊二酸的蓄积，以及程度较轻的3-羟基戊二酸和戊烯二酸的蓄积。异常代谢产物的表现差异很大，从严重有机酸尿症到戊二酸排泄仅轻微或间歇性升高甚至正常，这使得诊断有时很困难。在编码戊二酰辅酶A脱氢酶的基因中已鉴定出近100种致病突变。特定突变与戊二酸排泄量低或无排泄相关，但基因型与临床表型之间似乎没有相关性。GA I会导致独特的、与年龄和部位相关的神经病理后遗症。从妊娠后半期开始，额叶和颞叶皮质的成熟受到阻碍，导致额颞叶萎缩的特征性表现。在6至18个月大时，相对较轻的神经症状可能会因常见感染或常规免疫接种过程中的发热或分解代谢状态、手术所需的禁食或轻微头部受伤而加重。壳核和尾状核被破坏，导致永久性运动障碍，类似于脑瘫，范围从极度肌张力低下到舞蹈手足徐动症再到伴有痉挛的僵硬。最近，潜在的病理生理学已被确定为环境触发的、与年龄和部位相关的NMDA 2B受体亚型过度刺激。目前的治疗可预防90%以上接受前瞻性治疗的受影响婴儿发生脑退化。未经治疗，超过90%的受影响儿童将出现严重神经残疾。在脑损伤之前识别这种疾病对于治疗至关重要。GA I可通过串联质谱法进行的常规新生儿筛查中戊二酰肉碱升高来识别。如果未进行此项筛查，及时诊断取决于对相对非特异性的体格检查结果（如肌张力低下、易激惹、巨头畸形）的识别、神经影像学中提示性异常的检测以及通过气相色谱-质谱法进行的定量尿有机酸分析。
